PROJECT SUMMARY/ABSTRACT ? Research Project 2 Ebolaviruses cause the most severe hemorrhagic fevers in humans, with mortality rates up to 90%. They also are considered potential weapons for bioterrorism and biological warfare. We have isolated thousands of naturally-occurring human antibodies (Abs) that neutralize ebolaviruses and marburgviruses and protect against disease in animal models. One of the gaps in the field of filovirus antibody therapeutics is the lack of monoclonal antibodies that act against all of the major pathogenic species of ebolavirus (Zaire ebolavirus [EBOV], Bundibugyo ebolavirus [BDBV] and Sudan ebolavirus [SUDV]. The key requirements for successful treatment of filovirus infections with monoclonal antibodies (mAbs) may include (A) use of broad and potent mAbs, and (B) administration of an antibody or cocktail of mAbs binding to highly conserved viral epitopes. We propose here to perform advanced development of pan-ebolavirus and pan-marburgvirus human monoclonal antibody therapeutics. The work will be conducted with a panel of highly promising antibodies that are in hand, with the goal of identifying and selecting lead compounds and advancing preclinical development in preparation for a subsequent IND filing and clinical testing. The work is organized around several aims that seek to compare the protection of mAbs against various filoviruses in vitro and in vivo, and to select lead candidate members. In addition, mAbs will be characterized by their mechanism of action, isotype, and Fc glycosylation content. Cell lines for large-scale production of the lead candidates will be done in an effort to develop large-scale production and purification methods for the lead candidate antibodies. We have a highly interactive consortium of investigators with complementary expertise in human antibody discovery and engineering (Vanderbilt), filovirus biology and immunity (UTMB) and antibody production (Mapp Biopharmaceutical). The work promises to yield a best-in-class antibody preparation for broad and potent activity against ebolaviruses that can be used to treat or prevent human ebolavirus infections.